The present invention relates to a new process for the preparation of Erbstatin and Erbstatin analogs, which can be represented by the following formula (I) ##STR2## wherein R is hydrogen, a lower alkyl or a lower alkanoyl group;
n is an integer of 1 to 3; PA1 A is --CH.dbd.CH-- or --CH.sub.2 --CH.sub.2 --; PA1 R.sub.1 is hydrogen or a lower alkyl group, and PA1 R.sub.2 is a hydrogen or halogen atom.
In the present invention the lower alkyl group and the lower alkanoyl group means that the alkyl group part is a branched or straight alkyl group having 1 to 5 carbon atoms.
When n is 2 or 3, each single --OR group may be the same or different.
The halogen atom includes any one of fluorine, chlorine, bromine and iodine atoms.
The scope of the invention includes also all the possible isomers (e.g. Z and E isomers) of the compounds of formula (I) and the mixtures thereof.
Erbstatin is an antibiotic, produced by a strain of Streptomycetes [EP-A-213320], which inhibits tyrosine-specific protein kinase, e.g. it inhibits the phosphorylation of the epidermal growth factor receptor [J. Antibiot. 1986, 39, 170]. The Erbstatin analogs, falling within the scope of formula (I) above, are disclosed by EP-A-238868 and are described as having similar biological properties.
The introduction of an acylaminovinyl group in a phenol compound is a well known process in the art. This type of substitution has been previously achieved by many step procedures. The method described by W. K. Anderson et al. in J. Org. Chem. 52, 2945 (1987), for instance, begins as is shown in scheme A herebelow with the treatment of 2,5-dimethoxybenzaldehyde with nitromethane to give a nitrostyrene, which after conjugate addition of thiophenol gives a thioether. Hydride reduction and N-formylation provides a saturated formamide, which is converted to an enamide by an oxidation and elimination process. Final ether cleavage gives Erbstatin. ##STR3## According to the process described in EP-A-238868, the acylaminovinylation procedure is alternatively carried out as shown in following scheme B. ##STR4## wherein
R' is lower alkyl or lower alkanoyl and R.sub.1, R.sub.2 and n are as defined above.
The benzaldehyde of formula (B1) is subjected to a Wittig reaction with diethyl isocyanomethylphosphite of formula (B2) to give the isocyanovinyl-phenol compound of formula (B3), which is hydrolyzed to obtain the formylaminovinylphenol compound of formula (B4). In order to obtain acylaminovinyl-phenol compounds of general formula (B6) other two steps are necessary, that is, an acylation and a deformylation reaction. So as to obtain the acylaminoethylene analogs (B'7). The compounds of formula (B4) are hydrogenated in the presence of a catalyst to give the corresponding compounds (B'4) ##STR5## which are further subjected to acylation and deformylation reaction affording compounds of formula (B'7) ##STR6## Although the synthesis method described in EP-A-238868 has the advantage of being short, from the industrial point of view it has the following drawbacks: (a) use of commercially non available reagents, e.g. diethyl isocyanomethylphosphite of formula (B2); (b) use of expensive and highly sensitive bases, e.g. sodium bis(trimethylsilyl)amide is used in the Wittig reaction; and (c) application of a laboratory scale chromatographic procedure, i.e. preparative T.L.C.
A further method for the preparation of Erbstatin has been described by D. G. Hangauer in Tetrahedron Letters 27, 5799 (1986).
Noteworthy is that in this case a phenylactic acid derivative is used as starting material, instead of a benzaldehyde derivative. ##STR7## wherein TBS means t-butyldimethylsilyl.
The commercially available lactone (C1) is reduced with DIBAH to the triol (C2), which is protected by transformation into the trisilylether (C3).
Selective cleavage with HF and partial oxidation with pyridinium chlorochromate provides the aldehyde (C5). Condensation with DMF gives compound (C6), which is deprotected with Bu.sub.4 NF to give Erbstatin. Although this method possesses a good overall yield (38%), from the industrial point of view many objections can be raised, for example: application of several chromatographic purifications, use of highly corrosive HF, and use of special chromatographic techniques.
Another 6-step stereoselective synthesis of Erbstatin, starting from the commercially available 2,5-dihydroxycinnamic acid, has been described by R. L. Dow and M. J. Flynn (Pfizer Inc.) in Tetrahedron Letters 28, 2217 (1987), as shown in the following scheme D. ##STR8##
Accordingly, 2,5-dihydroxycinnamic acid is acetylated and then transformed in acyl azide (D4) via its acyl chloride. Thermal rearrangement generates the isocyanate (D5), which is reduced selectively to the formamide (D6). Final deprotection provides Erbstatin. Although the overall yields are good (36%) this synthetic method has the disadvantage of using sodium azide, which under certain conditions is highly explosive.
In conclusion none of the four above described synthesis methods meets all the criteria requested for an industrial process, especially from the point of view of safety, large-scale production, availability of intermediates and reagents at commercial quantities and prices, and of industrially acceptable purification methods. Therefore there is the need to develop a new synthetic method that overcomes these limitations and fulfills the criteria of a real industrial process.